Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species.

BACKGROUND: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests. RESULTS: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes. CONCLUSIONS: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.

Isomer-specific comparisons of the hydrolysis of synthetic pyrethroids and their fluorogenic analogues by esterases from the cotton bollworm Helicoverpa armigera.

The low aqueous solubility and chiral complexity of synthetic pyrethroids, together with large differences between isomers in their insecticidal potency, have hindered the development of meaningful assays of their metabolism and metabolic resistance to them. To overcome these problems, Shan and Hammock (2001) [7] therefore developed fluorogenic and more water-soluble analogues of all the individual isomers of the commonly used Type 2 pyrethroids, cypermethrin and fenvalerate. The analogues have now been used in several studies of esterase-based metabolism and metabolic resistance. Here we test the validity of these analogues by quantitatively comparing their hydrolysis by a battery of 22 heterologously expressed insect esterases with the hydrolysis of the corresponding pyrethroid isomers by these esterases in an HPLC assay recently developed by Teese et al. (2013) [14]. We find a strong, albeit not complete, correlation (r = 0.7) between rates for the two sets of substrates. The three most potent isomers tested were all relatively slowly degraded in both sets of data but three esterases previously associated with pyrethroid resistance in Helicoverpa armigera did not show higher activities for these isomers than did allelic enzymes derived from susceptible H. armigera. Given their amenability to continuous assays at low substrate concentrations in microplate format, and ready detection of product, we endorse the ongoing utility of the analogues in many metabolic studies of pyrethroids.

Heat-evolved microalgal symbionts increase coral bleaching tolerance.

Coral reefs worldwide are suffering mass mortalities from marine heat waves. With the aim of enhancing coral bleaching tolerance, we evolved 10 clonal strains of a common coral microalgal endosymbiont at elevated temperatures (31°C) for 4 years in the laboratory. All 10 heat-evolved strains had expanded their thermal tolerance in vitro following laboratory evolution. After reintroduction into coral host larvae, 3 of the 10 heat-evolved endosymbionts also increased the holobionts' bleaching tolerance. Although lower levels of secreted reactive oxygen species (ROS) accompanied thermal tolerance of the heat-evolved algae, reduced ROS secretion alone did not predict thermal tolerance in symbiosis. The more tolerant symbiosis exhibited additional higher constitutive expression of algal carbon fixation genes and coral heat tolerance genes. These findings demonstrate that coral stock with enhanced climate resilience can be developed through ex hospite laboratory evolution of their microalgal endosymbionts.

Targeted therapy for advanced renal cell carcinoma.

BACKGROUND: Advanced renal cell carcinoma has been resistant to drug therapy of different types and new types of drug therapy are needed. Targeted agents inhibit known molecular pathways involved in cellular proliferation and neoangiogenesis, the induction by the tumour of host microvascular networks. Angiogenesis is of special interest in the clear cell histologic subtype of renal cancer because of its vascularity and constitutively activated hypoxia-inducible path in the majority of tumours. OBJECTIVES: 1) To provide a systematic review of studies testing targeted agents.2) To identify the type and degree of clinical benefit, if any, of targeted agents over the prior standard of care, particularly any impact on overall survival. SEARCH STRATEGY: 1) Electronic search of CENTRAL, MEDLINE and EMBASE databases.2) Hand search of international cancer meeting abstract and other sources specified in the protocol. SELECTION CRITERIA: Randomized controlled studies of targeted agents in patients with advanced renal cell cancer reporting major remission rate or overall survival by allocation. Progression-free survival (PFS) was adopted as an additional outcome because PFS was a commonly chosen primary outcome, and because several pivotal studies allowed crossover from the control to the investigational arm after closure to accrual thereby making overall survival a problematic endpoint. DATA COLLECTION AND ANALYSIS: Nineteen fully eligible studies tested ten different targeted agents (Table 04). One additional study was excluded because no outcome data by allocation have been reported (Hutson 2007). For purposes of comparison, the studies were divided into three groups: Group 1 studies compared different doses of the same agents; Group 2 studies examined the impact of targeted agents in patients who had received prior cytokine or other systemic therapy; and Group 3 studies tested targeted agents in systemically naive patients, either against standard interferon-alfa or against another control therapy. Meta-analysis was not utilized because there were very few situations where the same agents had been tested in the same group in more than one study. MAIN RESULTS: In systemically untreated patients in studies using subcutaneous interferon-alfa as control therapy, the major findings were: 1) An improvement in overall survival has been demonstrated only with the use of weekly intravenous temsirolimus in patients with unselected renal cancer histology and adverse prognostic features (median survival 10.9 months versus 7.3 months for temsirolimus or interferon-alfa respectively, HR 0.73, P = 0.008 log rank, Hudes 2007). However, the chance of major remission was low and not improved with temsirolimus. 2) In patients with mostly good or intermediate prognostic risk with clear cell renal cancer, oral sunitinib improves the chance of major remission, the probability of symptomatic improvement, and freedom from disease progression (Motzer 2007); in a similar setting, the addition of biweekly intravenous bevacizumab to interferon-alfa also improved the chance of major remission and prolonged progression-free survival (Escudier 2007b); overall survival had not changed at the time of interim reporting of either study. In patients with clear cell renal cancers who had failed prior cytokine therapy, oral sorafenib gives a better quality of life than placebo as well as improved chance of being free of disease progression; overall survival may have improved but is hard to evaluate because of crossover of placebo-assigned patients after the study closed to accrual (Escudier 2007a). AUTHORS' CONCLUSIONS: Based on less than a decade of experience, some targeted agents with specified molecular targets have demonstrated clinically useful benefits over the previous standard of care for patients with advanced renal cancer. Much more research is required to fully establish the role of targeted agents in this condition.

Antigen clearing from porcine heart valves with preservation of structural integrity.

Bioprostheses currently used for replacement of diseased cardiovascular tissue are preserved and partially protected from immune rejection through chemical fixation. However, after implantation, chemically preserved (fixed) material has limited durability and lacks the ability to revitalize through cellular ingrowth and remodeling. As an alternative to fixation, we aimed at thoroughly removing antigens from tissue, leaving an intact scaffold, suitable for integration and revitalization in the host. Extensive washing of porcine heart valves with a mixture of two detergents (SDS and Triton X-100) yielded an intact matrix devoid of cells and depleted of soluble proteins that was minimally immunogenic in rabbits. A detailed characterization of the biomechanics and durability of the tissue is under way. If the lack of immunogenicity is confirmed in primates, our results would suggest that a detergent-washed, unfixed porcine heart valve can be an attractive non-inflammatory scaffold for heart valve regeneration in humans.

Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer.

PURPOSE: The Canadian multicenter trial for advanced non-small-cell lung cancer (NSCLC) reported survival benefit for chemotherapy when best supportive care was compared with vindesine-cisplatin (VP) and the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). We examined received drug delivery to document dose-intensity (DI) and total dose of drugs given to various groups in this patient population. PATIENTS AND METHODS: Plots of cumulatively received chemotherapy against time were used to evaluate drug delivery by regimen, major prognostic factors, and response status. RESULTS: Individual CAP patients show a narrow range of received DI, with the median similar to protocol. Drug delivery analysis exposed a wide range of received DI for both drugs in the more intensive VP regimen, and the median received DI was below protocol. The median received DI for cisplatin was still higher for VP than CAP, but only during the first 8 weeks of protocol treatment (20 v 10 mg/m2/wk); thereafter, the ongoing received cisplatin DI was the same (10 mg/m2/wk). The median received DI for cisplatin in each regimen was not influenced by stage, performance status, prior weight loss, sex, or response status. VP-treated patients received a higher total dose of cisplatin than CAP patients (median, 255 mg/m2 v 112.5 mg/m2; P < .0001). Median cisplatin total dose was similar for patients with a chemotherapy response or stable disease and threefold greater than for patients with progressive disease for both regimens. Although patients with chemotherapy response and stable disease had similar survival outcomes for both CAP and VP, the VP regimen had a higher proportion of patients without progressive disease (P = .004), which resulted in an overall survival advantage (P = .01). CONCLUSION: The major prognostic factors for advanced NSCLC do not exert their influence on outcome by affecting deliverable chemotherapy DI. Regimen and treatment response determined total dose. Because stable disease patients usually outnumber responding patients in advanced NSCLC trials, controlled studies should be performed that allow assessment of the impact of total received dose on outcome according to response status.

Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer.

PURPOSE: This phase II study was designed to assess the effects of mitoxantrone with prednisone in patients with metastatic prostate cancer who had progressed on hormonal therapy. The methods of assessment included quality-of-life analyses, pain indices, analgesic scores, and the National Prostatic Cancer Project (NPCP) criteria. PATIENTS AND METHODS: Patients received mitoxantrone 12 mg/m2 intravenously every 3 weeks plus prednisone 10 mg orally daily. All had a castrate serum testosterone and Eastern Cooperation Oncology Group (ECOG) performance status < or = 3, and had not received prior chemotherapy. Every 3 weeks, analgesic intake was scored, and a present pain intensity (PPI) record and visual analog scale (VAS) describing pain were collected. Every 6 weeks, the European Organization for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire plus a prostate-specific module were completed. A palliative response was defined as a decrease in analgesic score by > or = 50% or a decrease in PPI by > or = two integers without any increase in the other. RESULTS: Twenty-seven patients were entered onto the study. Nine of 25 (36%) assessable patients achieved a palliative response maintained for > or = two cycles (range, two to eight or more). Improvements in mean PPI and VAS pain scores after each cycle of therapy (P < .05) were seen. Quality-of-life analysis showed improvements in social and emotional functioning, and in pain and anorexia. Using NPCP criteria, one patient achieved a partial response (PR) and 12 had stable disease; one of seven patients with measurable disease had a PR. No serious nonhematologic toxicity was experienced, and there were no episodes of febrile neutropenia. CONCLUSION: Mitoxantrone with low-dose prednisone is a well-tolerated treatment regimen that has some beneficial effects on disease-related symptoms and quality of life for patients with advanced prostate cancer.

Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: A prospective randomized trial was conducted to determine whether the addition of concurrent cisplatin to preoperative or definitive radiation therapy in patients with muscle-invasive bladder cancer improved local control or survival. PATIENTS AND METHODS: Ninety-nine eligible patients with T2 to T4b transitional cell bladder cancer participated, 64% with cT3b or cT4. Patients and their physicians selected either definitive radiotherapy or precystectomy radiotherapy; patients were then randomly allocated to receive intravenous cisplatin 100 mg/m2 at 2-week intervals for three cycles concurrent with pelvic radiation, or to receive radiation without chemotherapy. Patients were stratified by clinical tumor stage and by radiation plan. The median follow-up duration is 6.5 years. RESULTS: The occurrence of distant metastases was the same in both study arms. However, 25 of 48 control patients have had a first recurrence in the pelvis, compared with 15 of 51 cisplatin-treated patients (P = .036). The pelvic relapse rate in the two groups was significantly reduced by concurrent cisplatin (P = .038, log-rank test) and this effect was preserved in a stepwise Cox regression model of prognostic factors (hazards ratio, 0.50; 90% confidence interval [CI], 0.29 to 0.86; P = .036). The hazard reduction was similar for both radiation plans. Pretreatment leukocytosis and high clinical stage were independent adverse factors in a Cox model of overall survival, but the effect of cisplatin was not significant. CONCLUSION: Concurrent cisplatin may improve pelvic control of locally advanced bladder cancer with preoperative or definitive radiation, but has not been shown to improve overall survival. The use of concurrent cisplatin had no detectable effect on distant metastases.

Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer.

PURPOSE: To evaluate the efficacy of an abbreviated treatment plan consisting of two cycles of chemotherapy plus thoracic irradiation in a population of limited-stage small-cell lung cancer (LSCLC) patients who were elderly, infirm, or noncompliant with standard-duration therapy. PATIENTS AND METHODS: Fifty-five LSCLC patients (median age, 73) were treated with one cycle of cyclophosphamide, doxorubicin, and vincristine (CAV) followed 3 weeks later by one cycle of etoposide and cisplatin (EP). Both regimens were administered at conventional full dose. Thoracic irradiation (20 to 30 Gy) was delivered concurrently with EP. RESULTS: Complete response occurred in 28 patients (51%) and partial response in 21 (38%). The median survival time was 54 weeks; the 2-year survival rate was 28% and the actual 5-year survival rate was 18%. Three patients died of toxicity. CONCLUSION: Elderly, infirm, or noncompliant LSCLC patients who are unable to receive standard-duration chemotherapy may have useful palliation and potential for long-term survival with abbreviated chemotherapy (two cycles) and thoracic irradiation.

Phase I/II trial of biweekly paclitaxel and cisplatin in the treatment of metastatic breast cancer.

PURPOSE: To determine the maximum-tolerated dose of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) administered biweekly with a fixed dose of cisplatin, to assess the toxicity, and to evaluate the activity of this combination in a phase I/II trial in metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women with metastatic breast cancer were enrolled; 27 were assessable for response and 29 for toxicity. All but two of the women had received prior adjuvant chemotherapy, with 23 receiving anthracyclines and six previous cisplatin. RESULTS: The initial starting dose of paclitxel 90 mg/m2 and cisplatin 60 mg/m2 became the phase II dose due to dose-limiting neutropenia. Responses were seen in 85% of assessable patients, with three patients (11%) achieving a complete response (CR) and 20 patients (14%) a partial response (PR), for an overall response rate of 85% (95% confidence interval [CI], 66% to 96%). The time to disease progression for patients who achieved a CR was 110 to 200 days, and for those with a PR, it was 96 to 377+ days, with a median time to progression of 7.1 months and a median response duration of 7.9 months. Sites of CR were skin, soft tissue, and lung, and all occurred in women with previous exposure to anthracyclines. Septic events were rare, with two grade 3 infections (7%), only one of which required hospital admission. There were no grade 4 nonhematologic toxicity and minimal grade 3 toxicity. A total of 251 chemotherapy cycles were given -- 16 with paclitaxel alone in five patients. Forty-five percent of patients required dose reductions, while 52% had delays due to neutropenia. CONCLUSION: Biweekly paclitaxel and cisplatin is an active combination in the treatment of metastatic breast cancer, including for patients with previous exposure to anthracyclines.

Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points.

PURPOSE: To investigate the benefit of chemotherapy in patients with symptomatic hormone-resistant prostate cancer using relevant end points of palliation in a randomized controlled trial. PATIENTS AND METHODS: We randomized 161 hormone-refractory patients with pain to receive mitoxantrone plus prednisone or prednisone alone (10 mg daily). Nonresponding patients on prednisone could receive mitoxantrone subsequently. The primary end point was a palliative response defined as a 2-point decrease in pain as assessed by a 6-point pain scale completed by patients (or complete loss of pain if initially 1 +) without an increase in analgesic medication and maintained for two consecutive evaluations at least 3 weeks apart. Secondary end points were a decrease of > or = 50% in use of analgesic medication without an increase in pain, duration of response, and survival. Health-related quality of life was evaluated with a series of linear analog self-assessment scales (LASA and the Prostate Cancer-Specific Quality-of-Life Instrument [PROSQOLI]), the core questionnaire of the European Organization for Research and Treatment of Cancer (EORTC), and a disease-specific module. RESULTS: Palliative response was observed in 23 of 80 patients (29%; 95% confidence interval, 19% to 40%) who received mitoxantrone plus prednisone, and in 10 of 81 patients (12%; 95% confidence interval, 6% to 22%) who received prednisone alone (P = .01). An additional seven patients in each group reduced analgesic medication > or = 50% without an increase in pain. The duration of palliation was longer in patients who received chemotherapy (median, 43 and 18 weeks; P < .0001, log-rank). Eleven of 50 patients randomized to prednisone treatment responded after addition of mitoxantrone. There was no difference in overall survival. Treatment was well tolerated, except for five episodes of possible cardiac toxicity in 130 patients who received mitoxantrone. Most responding patients had an improvement in quality-of-life scales and a decrease in serum prostate-specific antigen (PSA) level. CONCLUSION: Chemotherapy with mitoxantrone and prednisone provides palliation for some patients with symptomatic hormone-resistant prostate cancer.

Immunotherapy for advanced renal cell cancer.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest. SEARCH STRATEGY: A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to June 2004. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported remission or survival by allocation. Fifty-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 of these studies reported the one-year survival outcome. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alfa versus controls, and for two randomized studies of the value of initial nephrectomy prior to interferon-alfa in fit patients with metastases detected at the time of diagnosis. MAIN RESULTS: Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. It has been established that reduced dose interleukin-2 given by intravenous bolus or by subcutaneous injection provides equivalent survival to high dose interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two recent randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms: despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival by 4.8 months over interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of bevacizumab, an anti-vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo therapy though frequency of remissions or survival were not improved. AUTHORS' CONCLUSIONS: interferon-alfa provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.

A four base pair insertion polymorphism in the 3' untranslated region of the COL1A1 gene is highly informative for null-allele testing in patients with osteogenesis imperfecta type I.

In patients with osteogenesis imperfecta (OI) type I, a decrease in synthesis of type I collagen is usually observed as a result of a COL1A1 null allele. Testing for COL1A1 null alleles can be done using polymorphic markers in the coding region of the COL1A1 gene. Until now, only one marker for polymorphism in the 3' untranslated region (3' UTR) of the COL1A1 gene has been available. We have identified a 4 bp insertion in the 3' UTR of the COL1A1 gene localized downstream of the MnlI RFLP and used both markers in combination for the analysis of patients with OI type I. In a total of 50 patients, 28 showed heterozygosity for one of the two markers; 14 of them were shown to have a COL1A1 null allele.

The description of chemotherapy delivery: options and pitfalls.

Delivered and planned drug doses in chemotherapy trials are analyzed in relation to dose size, dose rate, and total drug delivery. Time-dose factors are presented in different ways, further exploring what may be misleading when comparing one treatment program with another. The time frame over which treatment intensity is to be calculated is recognized as arbitrary and not necessarily from start to end of treatment. Considerations for doses missed are presented. The cumulative-dose plot represents a new method of data presentation. This method graphically captures both intensity and total drug delivery per patient, and is helpful when analyzing trials designed to isolate treatment variables and improve the therapeutic index of available drugs.

Locoregional first recurrence after mastectomy: prospective cohort studies with and without immediate chemotherapy.

PURPOSE: To evaluate prospectively the impact of combination chemotherapy in the combined modality treatment of isolated first locoregional recurrence (LRR) following mastectomy for breast cancer. METHODS AND MATERIALS: Between 1979 and 1989, 120 chemotherapy-naive women with isolated LRR as first failure after mastectomy were prospectively identified, uniformly staged, and systematically followed. Treatment consisted of excision if feasible, radical locoregional radiotherapy, and a hormonal maneuver (unless estrogen receptor negative). The initial chemotherapy cohort also received 8 cycles of doxorubicin and cyclophosphamide. This was compared to a subsequent control cohort. RESULTS: For all patients, the 10-year actuarial relapse-free survival +/- 95% confidence interval was 42.1+/-9.2%, and overall survival was 56.8+/-9.1%. No difference was seen in locoregional control between cohorts. At 5 years, distant recurrence-free survival for chemotherapy and control cohort respectively was 75.4+/-10.8% and 60.7+/-12.5% (p = 0.33) and overall survival was 81.9%+/-9.6 and 74.3%+/-11.2 (p = 0.24). Univariate analysis showed no prognostic importance for any imbalance between cohorts. Cox modeling confirmed that complete resection was strongly associated with fewer LRR (hazard ratio [HR] 0.32, p = 0.001) and also with better overall survival (HR 1.82, p = 0.019). Chemotherapy produced a substantial reduction in risk of death (HR 0.72 CI 0.421-1.235, p = 0.23). CONCLUSIONS: In this prospective but nonrandomized study of treatment for first LRR, the risk of death in the later control cohort was 1.39 times the risk in the chemotherapy cohort but failed to reach statistical significance. The results justify further study.

Site of bronchodilatation with inhaled ipratropium bromide and fenoterol in normal subjects.

To assess the effectiveness and site of action of bronchodilatation with an inhaled anticholinergic bronchodilator, ipratropium bromide, and a beta adrenergic agonist, fenoterol, we measured the density dependence of maximal flow and the density dependence of pulmonary resistance using a digital computerized averaging circuit. Eight normal subjects were studied on two separate days, before and after the bronchodilators were administered in a double blind manner. Both drugs resulted in significant and equivalent bronchodilatation. However, there were no significant changes in the density dependence of maximal flow or pulmonary resistance with either agent. These results in normal subjects, therefore, do not support the hypothesis of a preferential site of action of inhaled anticholinergic agents and beta-adrenergic agents.

Mitomycin is active against refractory germ-cell tumors. A phase II study.

Mitomycin was used as single-agent therapy in seven male patients with nonseminomatous germ-cell tumors resistant to platinum analogues. The toxicity was high, especially hematological and pulmonary, in this heavily pretreated group. Mitomycin was active in this situation and one complete and one partial response of 18 and 20 weeks' duration, respectively, were seen.

Immunotherapy for advanced renal cell cancer.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alpha to other options. SEARCH STRATEGY: A search of MEDLINE, Cancerlit, EMBASE and Cochrane Library databases from 1966 through the end of 1999. Handsearches were made of the proceedings of the annual meetings of the American Urologic Association, ASCO, and biennial European ECCO meetings, and the references of identified studies. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported response or survival by allocation. Forty-two studies involving 4216 patients were eligible and reported response and 26 of these reported survival outcome (3089 patients). DATA COLLECTION AND ANALYSIS: Two independent reviewers abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment response (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alpha versus controls. MAIN RESULTS: The average response rate was 10.2 % (range by arm, 0 - 39%) and complete response rate was 3.2% (123/3852; n = 38 studies). Median survival averaged 11.6 months (range by arm, 6 - 28 months) and two-year survival averaged 22% (16 studies, range by arm 8 - 41%). There were no placebo-controlled studies and no randomized controlled studies examined survival for high dose interleukin-2 versus controls. Results from 6 studies (n = 963) indicate that interferon-alpha is superior to controls (OR for death at one year = 0.67, 95% CI 0.50 - 0.89. The pooled hazard ratio for survival of 0.78 (0.67 - 0.90) indicates that the treatment effect persisted until 24 months from randomization. The weighted average median improvement in survival was 2.6 months. Additional comparisons failed to prove a survival benefit from the addition of other agents to either modified schedules of interleukin-2 or to interferon-alpha. Dose-response studies examining survival for either agent could not be identified. The difference in response rate between arms was correlated with the difference in survival (P<0.001) suggesting that response rate difference may be a surrogate intermediate endpoint for survival. REVIEWER'S CONCLUSIONS: Interferon-alpha provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. Interleukin-2 has not been validated in controlled randomized studies.